Sequential 1,3-dipolar cycloaddition of nitrones to β-(2-aminophenyl) α,β-ynones and cyclocondensation: A new entry to the isoxazolino[4,5-c]quinoline ring

Article abstract of DOI:10.1002/ejoc.200800994

The reaction of β-(2-aminophenyl) α,β-ynones with N-methyl nitrones provides a simple and efficient entry to the isoxazol-Germany, 2009) ino[4,5-c]quinoline ring system through a sequential 1,3-dipolar cycloaddition/annulation process.

Full text of DOI:10.1002/ejoc.200800994

FULL PAPER
DOI: 10.1002/ejoc.200800994
Sequential 1,3-Dipolar Cycloaddition of Nitrones to β-(2-Aminophenyl)
α,β-Ynones and Cyclocondensation: A New Entry to the
Isoxazolino[4,5-c]quinoline Ring
Giorgio Abbiati,[a] Antonio Arcadi,[b] Fabio Marinelli,*[b] Elisabetta Rossi,[a] and
Mirella Verdecchia[b]
Keywords: Alkynones / Nitrones / Heterocycles / Cycloaddition / Polycycles
The reaction of β-(2-aminophenyl) α,β-ynones with N-methyl
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
nitrones provides a simple and efficient entry to the isoxazol- Germany, 2009)
ino[4,5-c]quinoline ring system through a sequential 1,3-di-
polar cycloaddition/annulation process.
Introduction
Isoxazolines represent a current synthetic target[6–10]
owing to their importance in medicinal chemistry. In par-
ticular, the isoxazoline nucleus represents a stable bio-
isosteric replacement for the amide bond, which is found in
many biologically active molecules and drugs such as anti-
biotics.[11] On the other hand, the polycyclic quinoline ring
system is also present in pharmacologically active sub-
stances.[5,12,13] Although there are various efficient pro-
cedures leading to isoxazolines, to the best of our knowl-
edge the synthesis of isoxazolino[4,5-c]quinolines 4 has not
been reported yet; only dehydrogenated analogues of 4,
namely isoxazolo[4,5-c]quinolines, have been synthe-
sized.[5,14–16] Consequently, we focused our efforts on the
development of a viable approach to the synthesis of 4.
Nitrones are useful and versatile intermediates in organic
synthesis; they behave as 1,3-dipoles in cycloaddition reac-
tions[17] and are particularly suitable for the construction of
structurally complex molecules such as nitrogen-containing
biologically active compounds[18] and fused or bridged ring
structures.[19] Alkynes undergo facile cycloaddition reac-
tions with nitrones under thermal conditions to give isox-
azolines and the regioselectivity is strongly affected by steric
and electronic factors.[20] Monosubstituted electron-rich al-
kynes give 5-substituted 4-isoxazolines as the main prod-
ucts, whereas electron-poor monosubstituted alkynes show
a strong tendency to afford 4-substituted 4-isoxazolines 3
with high regioselectivity (Scheme 1).[21] This is also the
The development of one-pot transformations for build-
ing up target compounds is a challenge in organic synthesis.
Performing more than one synthetic step in the same reac-
tion vessel represents a useful tool for saving time and en-
ergy, as well as for reducing the use of organic solvents in
the isolation and purification of intermediates. For these
reasons, the development of new sequential reactions is by
itself a considerable success en route to sustainable organic
chemistry.
As part of our ongoing research activities in this field,
we have investigated the sequential addition/annulation re-
actions of β-(2-aminophenyl) α,β-ynones 1. These deriva-
tives gave 2,4-disubstituted quinolines through sequential
nucleophilic addition/annulation reactions[1] or sequential
transition-metal-catalysed hydroarylation (hydrovinylation)/
annulation processes.[2,3] Moreover, we reported that se-
quential [2+2] cycloaddition of cycloalkanone enamines
with 1 followed by cyclocondensation afforded quinolines
cis-fused to different-sized carbocyclic rings.[4] In a related
process, the reactions of 1 with azides[1] or nitrile oxides[5]
resulted in the formation of quinoline derivatives cis-fused
to heteroaromatic triazole or isoxazole rings.
These synthetic methods can lead to the formation of
polycyclic quinolines that are not otherwise easily available.
We decided therefore to investigate the possibility of embed-
ding a different pentatomic heterocyclic ring into the fused
quinoline system.
[a] Istituto di Chimica Organica, Università degli Studi di Milano,
Via Venezian 21, 20133 Milano, Italy
[b] Dipartimento di Chimica, Ingegneria Chimica e Materiali, Uni-
versità dell’Aquila,
Via Vetoio, 67100 L’Aquila, Italy
Fax: +39-0862433753
E-mail: fmarinel@univaq.it
Scheme 1.
Eur. J. Org. Chem. 2009, 1027–1031
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi, M. Verdecchia
FULL PAPER
case for disubstituted alkynes such as ethyl phenylpro- Table 1. Synthesis of the isoxazolino[4,5-c]quinolines 4.[a]
piolate. This inversion of regioselectivity has been rational-
ized by FMO theory.[22]
On the basis of this knowledge, we envisaged that the
cycloaddition reaction of β-(2-aminophenyl) α,β-ynones 1
with nitrones 2 could represent a straightforward entry to
polycyclic compounds 4 through a sequential one-pot pro-
tocol (see Scheme 2). Herein we report the results of this
study.
Results and Discussion
The reaction between the α,β-ynone 1a and the nitrone
2a in toluene was chosen as a model system. As shown in
Scheme 2, we observed the formation of the isoxazol-
ino[4,5-c]quinoline 4a as a single regioisomer. The effect of
temperature and the amount of nitrone was briefly investi-
gated. The use of 2 equiv. of 2a at 110 °C is necessary to
attain the best yields; a lower molar excess gave unsatisfac-
tory results. The reaction can be also carried out at 80 °C
by prolonging the reaction time but, at least in the model
reaction, this resulted in lower efficiency.
Scheme 2.
The procedure was then extended to include different
combinations of β-(2-aminophenyl) α,β-ynones 1a–g and
nitrones 2a–d. The results are reported in Table 1.
The isoxazolino[4,5-c]quinolines 4 were isolated in mod-
erate-to-high yields as single regioisomers. According to our
previous studies,[1–5] the present process can be explained as
depicted in Scheme 3: regioselective 1,3-dipolar cycload-
dition of nitrones 2 to α,β-ynones 1 results in the formation
of alkenes 5, from which the quinoline nucleus is generated
by condensation between the amino and carbonyl groups.
[a] Reactions were carried out on a 0.5 mmol scale in dry toluene
(5 mL) with the molar ratio 1/2 = 1:2. [b] Racemic mixtures. [c]
Scheme 3.
1028
Isolated yields.
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Eur. J. Org. Chem. 2009, 1027–1031

A New Entry to the Isoxazolino[4,5-c]quinoline Ring
(t, J = 7.1 Hz, 3 H) ppm. 13C NMR: δ = 177.0, 165.7, 150.7, 140.0,
All compounds were identified on the basis of analytical
and spectroscopic data, and proposed structures are in
agreement with the experimental data of similar com-
pounds reported in the literature. In particular, the regio-
chemistries of compounds 4a and 4e were unambiguously
established by NOESY experiments and extended by anal-
ogy to the entire series. Diagnostic NOE interactions are
shown in Figure 1.
134.9, 133.9, 133.0, 129.8, 129.2, 118.0, 114.8, 103.4, 93.4, 92.5,
61.6, 14.3 ppm. IR (KBr): ν = 2150, 1730, 1640 cm–1. MS (EI): m/z
˜
(%) = 293 (100) [M]+. C18H15NO3 (293.32): calcd. C 73.71, H 5.15,
N 4.78; found C 73.47, H 5.13, N 4.80.
4-[3-(2-Aminophenyl)prop-2-ynoyl]benzonitrile (1f): M.p. 124–
125 °C. 1H NMR: δ = 8.29 (d, J = 8.3 Hz, 2 H), 7.82 (d, J = 8.3 Hz,
2 H), 7.48 (dd, J1 = 1.3, J2 = 8.1 Hz, 1 H), 7.34–7.25 (m, 1 H),
6.79–6.72 (m, 2 H), 4.55 (br. s, 2 H) ppm. 13C NMR: δ = 175.9,
150.8, 139.9, 133.9, 133.3, 132.5, 129.7, 118.1, 117.9, 117.0, 114.9,
103.1, 93.5, 93.2 ppm.. IR (KBr): ν = 2200, 2150, 1630 cm–1. MS
˜
(EI): m/z (%) = 246 (100) [M]+. C16H10N2O (246.26): calcd. C
78.03, H 4.09, N 11.38; found C 78.29, H 4.09, N 11.34.
N-[(4-Methylphenyl)methylene]methanamine N-Oxide (2a): M.p.
114–115 °C. 1H NMR: δ = 8.11 (d, J = 8.2 Hz, 2 H), 7.32 (s, 1 H),
7.20 (d, J = 8.2 Hz, 2 H), 3.82 (s, 3 H), 2.36 (s, 3 H) ppm. 13C
NMR: δ = 140.8, 135.1, 129.1, 128.4, 127.9, 54.2, 21.6 ppm. IR
(KBr): ν = 1590, 1410 cm–1. MS (EI): m/z (%) = 149 (100) [M]+.
˜
C9H11NO (149.19): calcd. C 72.46, H 7.43, N 9.39; found C 72.58,
H 7.42, N 9.40.
Figure 1. Diagnostic NOE interactions as well as significant proton
chemical shifts for compounds 4a and 4e.
N-[(2E)-3-Phenylprop-2-enylidene]methanamine N-Oxide (2b): M.p.
As shown in Table 1, the reaction tolerates various func-
tional groups, such as the nitrile (entry 10), ester (entry 9)
and keto (entries 1 and 2) groups; vinylic (entries 1, 2, 6 and
7) and heteroarylic (entry 5) substituents are also allowed
on the isoxazoline moiety. Moreover the isoxazolino[4,5-c]-
quinoline 4l, substituted on the benzene ring of the quino-
line, can also be obtained in good yield.
1
86–88 °C. H NMR: δ = 7.51–7.21 (m, 7 H), 6.95 (d, J = 16.2 Hz,
1 H), 3.71 (s, 3 H) ppm. 13C NMR: δ = 137.7, 137.2, 135.8, 128.9,
128.6, 127.0, 118.1, 52.0 ppm. IR (KBr): ν = 1550, 1400 cm–1. MS
˜
(EI): m/z (%) = 161 (100) [M]+. C10H11NO (161.20): calcd. C 74.51,
H 6.88, N 8.69; found C 74.69, H 6.89, N 8.68.
N-[(2E)-3-(2-Furyl)prop-2-enylidene]methanamine N-Oxide (2c):
1
M.p. 128–129 °C. H NMR: δ = 7.44 (s, 1 H), 7.23–7.17 (m, 2 H),
6.95–6.83 (m, 1 H), 6.50–6.43 (m, 2 H), 3.73 (s, 3 H) ppm. 13C
NMR: δ = 152.4, 143.7, 136.3, 124.0, 116.3, 112.1, 111.7, 52.2 ppm.
IR (KBr): ν = 1610, 1570, 1390 cm–1. MS (EI): m/z (%) = 151 (100)
Conclusions
˜
[M]+. C9H9NO2 (151.16): calcd. C 63.56, H 6.00, N 9.27; found C
63.35, H 6.01, N 9.24.
The results reported here prove that the sequential 1,3-
dipolar cycloaddition/cyclocondensation reaction involving
β-(2-aminophenyl) α,β-ynones 1 and N-methyl nitrones 2a–
d represents a simple and efficient entry to the isoxazol-
ino[4,5-c]quinoline ring system. The procedure allows the
easy assembly of a complex polycyclic structure by sequen-
tial double annulation starting from the easily available acy-
clic substrates. The reaction is also valuable in terms of
“atom economy”[23] as the final product represents simply
the sum of the reactants with the loss of a water molecule.
N-[2-Furylmethylene]methanamine N-Oxide (2d): M.p. 90–91 °C.
1H NMR: δ = 7.75 (d, J = 3.5 Hz, 1 H), 7.57 (s, 1 H), 7.48 (d, J =
1.4 Hz, 1 H), 6.56–6.53 (m, 1 H), 3.82 (s, 3 H) ppm. 13C NMR: δ
= 146.6, 143.4, 126.0, 114.9, 112.0, 52.6 ppm. IR (KBr): ν = 1600,
˜
1480, 1400 cm–1. MS (EI): m/z (%) = 125 (100) [M]+. C6H7NO2
(125.13): calcd. C 57.59, H 5.64, N 11.19; found C 57.69, H 5.63,
N 11.17.
General Procedure for the Synthesis of Isoxazolino[4,5-c]quinolines
4: Nitrones 8 (1.00 mmol) were added to solutions of the β-(2-ami-
noaryl) α,β-ynones 1 (0.5 mmol) in dry toluene (8 mL). The mix-
tures were heated at reflux at 110 °C until disappearance of 1 (GC–
MS and TLC analysis) and then concentrated in vacuo. The crude
residues were purified by flash chromatography on silica gel (hex-
ane/ethyl acetate mixtures as mobile phases) to yield compounds
4.
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded at
200 MHz in CDCl3 with a Bruker AC 200 spectrometer. IR spectra
were recorded with a Perkin–Elmer 683 spectrometer. Only the
most significant IR absorptions are given. EI mass spectra were
recorded with a Saturn 2000T GC/MS spectrometer. CHN analyses
were performed with an Eager 200 analyser. The synthesis of β-(2-
aminoaryl) α,β-ynones 1 has been described previously.[3] Com-
pounds 1a–d and 1g have previously been characterized. Nitrones
2a–d were obtained from N-methylhydroxylamine hydrochloride
and the corresponding aldehydes following the procedure reported
for the synthesis of N-(phenylmethylene)methanamine N-oxide.[24]
4a: Yield 67%; 121 mg were obtained from 120 mg of 1a and
136 mg of 2a. Hexane/ethyl acetate, 75:25, v/v, as the mobile phase;
1
m.p. 120–122 °C. H NMR: δ = 8.17 (d, J = 8.5 Hz, 1 H), 8.01 (d,
J = 7.9 Hz, 1 H), 7.91 (d, J = 8.3 Hz, 2 H), 7.74 (d, J = 8.3 Hz, 2
H), 7.81–7.71 (m, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 6.96 (d, J =
8.1 Hz, 2 H), 6.89 (d, J = 8.1 Hz, 2 H), 5.56 (s, 1 H, NCH), 3.11
(s, 3 H, NCH3), 2.57 (s, 3 H), 2.20 (s, 3 H) ppm. 13C NMR: δ =
197.7, 160.4, 154.8, 149.5, 143.4, 138.1, 137.0, 130.6, 129.5, 129.3,
129.0, 128.7, 128.3, 127.5, 126.4, 121.8, 116.4, 114.9, 75.1 (CH-N),
Ethyl 4-[3-(2-Aminophenyl)prop-2-ynoyl]benzoate (1e): M.p. 123–
125 °C. 1H NMR: δ = 8.26 (d, J = 8.6 Hz, 2 H), 8.17 (d, J = 8.6 Hz,
2 H), 7.48 (dd, J1 = 1.6, J2 = 8.4 Hz, 1 H), 7.31–7.22 (m, 1 H),
6.77–6.68 (m, 2 H), 4.60 (br. s, 2 H), 4.42 (q, J = 7.1 Hz, 2 H), 1.42
47.1 (Me-N), 26.6, 21.0 ppm. IR (KBr): ν = 1670, 1590 cm–1. MS
˜
(EI): m/z (%) = 394 (100) [M]+, 303 (49). C26H22N2O2 (394.47):
calcd. C 79.16, H 5.62, N 7.10; found C 78.93, H 5.60, N 7.12.
Eur. J. Org. Chem. 2009, 1027–1031
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1029

G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi, M. Verdecchia
FULL PAPER
4b: Yield 81%; 163 mg were obtained from 130 mg of 1a and
4g: Yield 86%; 161 mg were obtained from 120 mg of 1c and
160 mg of 2b. Hexane/ethyl acetate, 75:25, v/v, as the mobile phase; 151 mg of 2b. Hexane/ethyl acetate, 80:20, v/v, as the mobile phase;
1
m.p. 94–96 °C.1H NMR: δ = 8.17 (d, J = 8.5 Hz, 1 H), 8.04 (d, J m.p. 145–147 °C. H NMR: δ = 8.14 (d, J = 8.5 Hz, 1 H), 7.96 (d,
= 8.5 Hz, 2 H), 7.93 (d, J = 8.5 Hz, 2 H), 8.05–7.95 (m, 1 H), 7.80–
7.71 (m, 1 H), 7.57 (t, J = 7.1 Hz, 1 H), 7.20–7.08 (m, 5 H), 6.31
(d, J = 15.9 Hz, 1 H), 6.05 (dd, J1 = 15.9, J2 = 6.8 Hz, 1 H), 5.27
J = 8.17 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 2 H), 7.75–7.68 (m, 1 H),
7.51 (t, J = 7.2 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.20–7.13 (m,
5 H), 6.32 (d, J = 15.8 Hz, 1 H), 6.07 (dd, J1 = 15.8, J2 = 6.7 Hz,
(d, J = 6.8 Hz, 1 H, NCH), 3.13 (s, 3 H, NCH3), 2.59 (s, 3 H) ppm. 1 H), 5.22 (d, J = 6.7 Hz, 1 H, NCH), 3.10 (s, 3 H, NCH3) ppm.
13C NMR: δ = 197.6, 160.2, 154.8, 149.5, 143.4, 137.2, 135.9, 133.0, 13C NMR: δ = 160.2, 154.7, 149.4, 137.5, 135.9, 135.3, 132.9, 130.5,
130.6, 129.4, 128.8, 128.4, 128.0, 126.5, 126.4, 125.9, 121.7, 115.3,
115.0, 73.1 (CH-N), 46.6 (Me-N), 26.6 ppm. IR (KBr): ν = 1680,
129.9, 129.3, 128.7, 128.5, 128.0, 126.5, 126.1, 121.6, 115.0, 114.9,
73.0 (CH-N), 46.6 (Me-N) ppm. IR (KBr): ν = 1620, 1590,
˜
˜
1620 cm–1. MS (EI): m/z (%) = 406 (96) [M]+, 378 (82), 208 (100). 1490 cm–1. MS (EI): m/z (%) = 398 (37) [M]+, 397 (29), 396 (82),
C27H22N2O2 (406.48): calcd. C 79.78, H 5.46, N 6.89; found C
80.00, H 5.47, N 6.86.
370 (15), 207 (100). C25H19ClN2O (398.88): calcd. C 75.28, H 4.80,
N 7.02; found C 75.51, H 4.79, N 7.03.
4c: Yield 60%; 122 mg were obtained from 135 mg of 1a and
4h: Yield 58%; 106 mg were obtained from 120 mg of 1c and
155 mg of 2c. Hexane/ethyl acetate, 75:25, v/v, as the mobile phase; 142 mg of 2c. Hexane/ethyl acetate, 80:20, v/v, as the mobile phase;
1
1
m.p. 82–84 °C. H NMR: δ = 8.16 (d, J = 8.1 Hz, 1 H), 8.06 (d, J m.p. 105–106 °C. H NMR (300 MHz): δ = 8.15 (d, J = 8.6 Hz, 1
= 8.2 Hz, 2 H), 7.97 (d, J = 8.2 Hz, 2 H), 7.99 –7.93 (m, 1 H), H), 7.98 (d, J = 8.3 Hz, 1 H), 7.85 (d, J = 8.5 Hz, 2 H), 7.79–7.72
7.79–7.70 (m, 1 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.22 (d, J = 1.6 Hz,
(m, 1 H), 7.52, (t, J = 7.5 Hz, 1 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.27
1 H), 6.26–6.04 (m, 1 H), 6.84 (d, J = 17.7 Hz, 1 H), 6.09–6.03 (m, (d, J = 1.7 Hz, 1 H), 6.32–6.29 (m, 1 H), 6.19 (d, J = 15.8 Hz, 1
2 H), 5.25 (d, J = 5.8 Hz, 1 H, NCH), 3.10 (s, 3 H, NCH3), 2.62
(s, 3 H) ppm. 13C NMR: δ = 197.7, 160.3, 154.6, 151.6, 149.5,
143.4, 142.3, 137.3, 130.6, 129.4, 128.8, 128.5, 126.4, 124.3, 121.7,
120.9, 115.1, 115.0, 111.3, 109.1, 72.3 (CH-N), 46.7 (Me-N),
H), 6.14 (d, J = 3.3 Hz, 1 H), 6.08 (dd, J1 = 15.8, J2 = 6.0 Hz, 1
H), 5.22 (d, J = 6.0 Hz, 1 H, NCH); 3.11 (s, 3 H, NCH3) ppm. 13
NMR: δ = 160.6, 155.0, 152.0, 149.9, 142.7, 137.9, 135.7, 131.0,
C
130.2, 129.7, 129.2, 126.5, 124.7, 122.0, 121.2, 115.4, 115.1, 111.7,
26.7 ppm. IR (KBr): ν = 1680, 1630 cm–1. MS (EI): m/z (%) = 365
109.5, 72.6 (CH-N), 47.1 (Me-N) ppm. IR (KBr): ν = 1630,
˜
˜
(100) [M – OCH3]+, 364 (50), 322 (90). C25H20N2O3 (396.44): calcd. 1590 cm–1. MS (EI): m/z (%) = 389 (9) [M]+, 388 (34), 387 (41),
C 75.74, H 5.08, N 7.07; found C 75.51, H 5.09, N 7.09.
386 (100), 295 (80). C23H17ClN2O2 (388.85): calcd. C 71.04, H 4.41,
N 7.20; found C 71.10, H 4.40, N 7.22.
4d: Yield 59%; 108 mg were obtained from 120 mg of 1b and
142 mg of 2a. Hexane/ethyl acetate, 85:15, v/v, as the mobile phase; 4i: Yield 87%; 177 mg were obtained from 140 mg of 1d and
1
m.p. 78–80 °C. H NMR: δ = 8.14 (d, J = 8.5 Hz, 1 H), 7.99 (d, J 149 mg of 2a. Hexane/ethyl acetate, 90:10, v/v, as the mobile phase;
1
= 7.2 Hz, 1 H), 7.72–7.68 (m, 1 H), 7.65 (d, J = 8.8 Hz, 2 H), 7.49
(t, J = 7.8 Hz, 1 H), 7.02–6.85 (m, 6 H), 5.55 (s, 1 H, NCH), 3.80
(s, 3 H), 3.10 (s, 3 H, NCH3), 2.24 (s, 3 H) ppm. 13C NMR: δ =
160.3, 160.1, 155.8, 149.5, 137.9, 136.1, 131.8, 130.7, 130.3, 129.9,
m.p. 74–76 °C. H NMR: δ = 8.15 (d, J = 8.5 Hz, 1 H); 8.03 (d, J
= 8.2 Hz, 1 H), 7.80–7.70 (m, 3 H), 7.59–7.50 (m, 2 H), 7.46 (t, J
= 8.0 Hz, 1 H), 6.98 (d, J = 8.0 Hz, 2 H), 6.89 (d, J = 8.0 Hz, 2
H), 5.51 (s, 1 H, NCH), 3.12 (s, 3 H, NCH3), 2.22 (s, 3 H) ppm.
129.3, 127.3, 125.6, 121.7, 115.6, 114.8, 113.8, 75.0 (CH-N), 55.3, 13C NMR: δ = 160.6, 154.6, 149.6, 139.8, 138.5, 136.3, 131.9 (q,
47.3 (Me-N), 21.1 ppm. IR (KBr): ν = 1600, 1490 cm–1. MS (EI): JC-F = 1 Hz), 130.9, 130.7 (q, JC-F = 32 Hz, C-CF3), 129.6, 129.5,
˜
m/z (%) = 382 (100) [M]+, 291 (31). C25H22N2O2 (382.45): calcd. C 129.0, 127.8, 126.6, 125.7 (q, JC-F = 4 Hz), 125.5 (q, JC-F = 4 Hz),
78.51, H 5.80, N 7.32; found C 78.22, H 5.77, N 7.32.
124.2 (q, JC-F = 272 Hz, CF3), 122.1, 116.8, 115.1, 75.6 (CH-N),
55.6, 47.3 (Me-N), 21.3 ppm. IR (KBr): ν = 1620, 1590, 1500 cm–1.
˜
4e: Yield 84%; 165 mg were obtained from 130 mg of 1c and
151 mg of 2a. Hexane/ethyl acetate, 85:15, v/v, as the mobile phase;
MS (EI): m/z (%) = 420 (100) [M]+, 406 (9), 330 (75). C25H19F3N2O
(420.42): calcd. C 71.42, H 4.56, N 6.66; found C 71.21, H 4.64, N
6.64.
1
m.p. 115–118 °C. H NMR: δ = 8.14 (d, J = 8.5 Hz, 1 H), 8.00 (d,
J = 8.0, Hz, 1 H), 7.73 (t, J = 7.2 Hz, 1 H), 7.59–7.47 (m, 3 H),
7.29 (d, J = 8.4 Hz, 2 H), 6.98 (d, J = 8.0 Hz, 2 H), 6.89 (d, J = 4j: Yield 50%; 94 mg were obtained as an oil from 130 mg of 1e
8.0 Hz, 2 H), 5.50 (s, 1 H, NCH), 3.09 (s, 3 H, NCH3), 2.23 (s, 3 and 132 mg of 2a. Hexane/ethyl acetate, 85:15, v/v, as the mobile
H) ppm. 13C NMR: δ = 160.3, 154.8, 149.4, 138.1, 137.4, 135.0,
130.5, 129.8, 129.4, 129.3, 128.5, 127.4, 126.1, 121.8, 116.0, 114.8,
phase. 1H NMR: δ = 8.17 (d, J = 8.5 Hz, 1 H), 8.02, (two overlap-
ping doublets, J = 8.3 Hz, 3 H); 7.80–7.68 (m, 1 H), 7.03 (d, J =
75.0 (CH-N), 47.2 (Me-N), 21.1 ppm. IR (KBr): ν = 1620, 1590, 8.3 Hz, 2 H), 7.55 (t, J = 7.4 Hz, 1 H), 6.97 (d, J = 8.1 Hz, 2 H),
˜
1540 cm–1. MS (EI): m/z (%) = 388 (35), 386 (100) [M]+, 297 (26), 6.88 (d, J = 8.1 Hz, 2 H), 5.55 (s, 1 H, NCH), 4.38 (q, J = 7.1 Hz,
295 (82). C24H19ClN2O (386.87): calcd. C 74.51, H 4.95, N 7.24;
found C 74.73, H 4.94, N 7.22.
2 H), 3.12 (s, 3 H, NCH3), 2.22 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3
H) ppm. 13C NMR: δ = 166.3, 160.3, 155.0, 149.4, 143.2, 138.1,
133.0, 130.6, 129.8, 129.5, 129.4, 129.2, 128.4, 127.3, 126.3, 121.8,
116.4, 114.9, 75.0 (CH-N), 61.1, 47.2 (Me-N), 21.1, 14.3 ppm. IR
4f: Yield 43%; 75 mg were obtained from 123 mg of 1c and 120 mg
of 2d. Hexane/ethyl acetate, 85:15, v/v, as the mobile phase; m.p.
93–94 °C. 1H NMR: δ = 8.15 (d, J = 8.5 Hz, 1 H), 7.98 (d, J =
8.2 Hz, 1 H), 7.76 (t, J = 8.5 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 2 H),
7.53 (t, J = 7.03 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.31–7.30 (m,
1 H), 6.20–6.17 (m, 1 H), 5.88 (d, J = 3.0 Hz, 1 H), 5.68 (br. s, 1
(neat): ν = 1720, 1630, 1590, 1500 cm–1. MS (EI): m/z (%) = 424
˜
(25) [M]+, 410 (13), 205 (100). C27H24N2O3 (424.49): calcd. C 76.39,
H 5.70, N 6.60; found C 76.10, H 5.68, N 6.62.
4k: Yield 61%; 117 mg were obtained from 125 mg of 1f and
H, NCH), 3.08 (s, 3 H, NCH3) ppm. 13C NMR: δ = 161.0, 154.4, 151 mg of 2a. Hexane/ethyl acetate, 80:20, v/v, as the mobile phase;
1
151.4, 149.6, 143.1, 142.3, 137.4, 135.2, 130.7, 130.0, 129.5, 129.4,
128.7, 126.2, 121.8, 110.6, 109.3, 68.3 (CH-N), 46.6 (Me-N),
m.p. 83–85 °C. H NMR: δ = 8.15 (d, J = 8.5 Hz, 1 H), 8.03 (d, J
= 8.2 Hz, 1 H), 7.81–7.71 (m, 1 H), 7.70 (d, J = 8.2 Hz, 2 H), 7.59
(d, J = 8.2 Hz, overlapped with a multiplet, 3 H), 6.99 (d, J =
29.7 ppm. IR (KBr): ν = 1620, 1590, 1490 cm–1. MS (EI): m/z (%)
˜
= 298 (27), 297 (48), 296 (72) [M + H – C4H3O]+, 295 (100). 8.0 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 2 H), 5.52 (s, 1 H, NCH); 3.13
C21H15ClN2O2 (362.81): calcd. C 69.52, H 4.17, N 7.72; found C (s, 3 H, NCH3), 2.24 (s, 3 H) ppm. 13C NMR: δ = 160.6, 153.8,
69.33, H 4.17, N 7.74.
149.4, 143.2, 138.4, 136.0, 132.0, 130.8, 129.4, 129.2, 127.6, 126.7,
1030
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1027–1031

A New Entry to the Isoxazolino[4,5-c]quinoline Ring
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2668.
121.9, 118.6, 116.5, 114.9, 112.4, 75.3 (CH-N), 47.0 (Me-N),
21.1 ppm. IR (KBr): ν = 2200, 1630, 1590, 1500 cm–1. MS (EI):
˜
m/z (%) = 377 (100) [M]+, 362 (10), 286 (94). C25H19N3O (377.44):
calcd. C 79.55, H 5.07, N 11.13; found C 79.59, H 5.08, N 11.11.
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4l: Yield 68%; 134 mg were obtained from 135 mg of 1g and
140 mg of 2a. Hexane/ethyl acetate, 92:8, v/v, as the mobile phase;
m.p. 55–56 °C. H NMR: δ = 7.44–7.40 (m, 1 H); 7.32–7.15 (m, 3
1449–1451.
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4984.
1
H), 6.94–6.78 (m, 4 H), 6.74 (d, J = 8.1 Hz, 2 H), 5.36 (s, 1 H,
NCH), 3.76 (s, 3 H), 3.14 (s, 3 H, NCH3), 2.18 (s, 3 H) ppm. 13C
NMR: δ = 158.3, 156.5, 154.5 (dd, JC-F = 2, JC-F = 1 Hz, C quat.),
137.8, 137.4 (dd, JC-F = 12, JC-F = 2 Hz, C quat.), 136.2, 131.3,
130.6, 129.0, 128.1, 127.2, 121.6 (t, JC-F = 0.02 Hz, C quat.), 121.3,
116.4 (dd, JC-F = 11, JC-F = 4 Hz, C quat.), 110.8, 105.8 (dd, JC-F
= 23, JC-F = 29 Hz, C-H), 101.5 (dd, JC-F = 23, JC-F = 5 Hz, C-
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H), 75.7 (CH-N), 55.6, 47.2 (Me-N), 21.2 ppm. IR (neat): ν = 1600,
˜
1590, 1550 cm–1. MS (EI): m/z (%)
=
418 (100) [M]+.
C25H20F2N2O2 (418.44): calcd. C 71.76, H 4.82, N 6.69; found C
72.03, H 4.80, N 6.72.
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Acknowledgments
This work was supported by the Ministero dell’Università e della
Ricerca (Rome) and the University of L’Aquila.
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Received: October 13, 2008
Published Online: January 16, 2009
Eur. J. Org. Chem. 2009, 1027–1031
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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